Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate

BackgroundInhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved.ObjectiveWe investigated whether or not bronchial responsiveness to leukotriene (LT) D4 is reduced by fluticasone propionate in subjects with asthma.MethodsIn 13 subjects with mild asthma, inhalation challenges with methacholine and LTD4 were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 μg, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE4 concentrations as an index of cysteinyl-leukotriene biosynthesis.ResultsFluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD20 FEV1, and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD4 in the same subjects was unaffected by fluticasone, as were urinary LTE4 concentrations.ConclusionThese new data indicate that neither the biosynthesis nor the actions of leukotrienes appear to be sensitive to inhaled corticosteroids.Clinical implicationsThe study provides mechanistic support for the additive therapeutic efficacy of antileukotrienes and inhaled corticosteroids in asthma.